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Novel Cyclic Amino Benzoic Acid Derivative

Inactive Publication Date: 2007-10-25
KYORIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0115] The novel cyclic amino benzoic acid derivative or the addition salt thereof according to the present invention has excellent human PPAR α transcription activating ability, and exhibits excellent lipid lowering activity in a living body.
[0116] These compounds of the present invention are effective as a lipid lowering agent, in particular, as a lipid lowering agent in liver and an inhibitor against development of arteriosclerosis.

Problems solved by technology

Statin drugs, however, are poor in free fatty acid and triglyceride lowering ability, and fibrate drugs are poor in cholesterol lowering ability.
These endogenous unsaturated fatty acid derivatives are instable in both metabolic and chemical aspects, so that they cannot be provided as pharmaceuticals.
However, for this compound, no report about PPARα agonist activity is found.
However, no reports about PPARα agonist activity are found for these compounds.
However, no report about PPARα agonist activity is found for these compounds.
Furthermore, examples in patent specification lack description on a compound having a cyclic amino group.
However, no report about PPARα agonist activity of this compound is found.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

reference example 1

1-benzyl-2-oxoperhydroazepine

[0250]

[0251]ε-Caprolactum (3.00 g, 26.5 mmol) was dissolved in tetrahydrofuran (30 mL). To this solution, potassium hydride (3.34 g, 29.2 mmol) was added and the mixture was stirred at room temperature for 10 min. Benzyl chloride (3.36 mL, 29.2 mmol) and sodium iodide (100 mg) were added and the reaction mixture was further stirred at room temperature for 3 hours. Subsequently, water was added and the mixture was extracted with ethylacetate. The extract was washed with brine, dried over magnesium sulfate and concentrated. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 3.04 g (57%) of the desired compound as a colorless oil.

[0252]1H NMR (400 MHz, CDCl3) δ 1.46-1.51 (2H, m), 1.66-1.74 (4H, m), 2.60-2.62 (2H, m), 3.28-3.30 (2H, m), 4.59 (2H, s), 7.25-7.33 (5H, m).

[0253] FAB+ (m / z): 204 (M+H).

reference example 2

Methyl 1-benzyl-2-oxoperhydroazepine-3-carboxylate

[0254]

[0255] Diisopropylamine (2.95 mL, 21.0 mmol) and n-butyllithium (11.3 mL, 18.0 mmol) were dissolved in diethyl ether (50 mL) at −78° C. and the mixture was stirred for 10 min. 1-benzylperhydroazepine (3.04 g, 15.0 mmol) in diethyl ether (3 mL) was then added and the mixture was further stirred at room temperature for 10 min. The mixture was then stirred for another 10 min while bubbled with carbon dioxide. Subsequently, the reaction mixture was added to ice water and the aqueous layer was collected. 2 mol / L hydrochloric acid was added to make the mixture acidic. The mixture was then extracted with ethyl acetate and the extract washed with brine and dried over magnesium sulfate, followed by evaporation of the solvent. The resulting colorless oil (2.97 g) was dissolved in a 10% hydrogen chloride / methanol solution and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated. Water was added to th...

reference example 3

1-Benzyl perhydroazepin-3-yl methanol

[0258]

[0259] Methyl 1-benzyl-2-oxoperhydroazepine-3-carboxylate (2.39 g, 9.15 mmol) was dissolved in tetrahydrofuran (50 mL). To this solution, lithium aluminum hydride (868 mg, 18.3 mmol) was added and the mixture was stirred for 2 hours while being refluxed. Subsequently, ice water and a 10% aqueous sodium hydroxide solution were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then filtered through Celite. The filtrate was extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) hexane ethyl acetate=20:1->3:1) gave 1.30 g (65%) of the desired compound as a colorless oil.

[0260]1H NMR (400 MHz, CDCl3) δ 1.49-1.65 (3H, m), 1.70-1.86 (4H, m), 2.22-2.29 (1H, m), 2.70-2.80 (3H, m), 3.45 (1H, dd, J=10.4, 4.3 ...

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Abstract

The present invention relates to cyclic amino benzoic acid derivatives which are effective in therapy of lipid metabolism abnormality, diabetes and the like as a human peroxisome proliferators-activated receptor (PPAR) agonist, in particular, as an agonist against human PPARα isoform, and addition salts thereof, and pharmaceutical compositions containing these compounds. A cyclic amino benzoic acid derivative represented by the general formula (1) [wherein a ring Ar represents an aryl group which may have substituent, or the like; Y represents a C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, or the like; Z represents an oxygen atom, sulfur atom or —(CH2)n— (n represents 0, 1 or 2); X represents a hydrogen atom, halogen atom, lower alkyl group which may be substituted with a halogen atom, or the like; R represents a hydrogen atom or lower alkyl group, and —COOR substitutes for an ortho position or metha position of binding position of ring W] or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD [0001] The present invention relates to cyclic amino benzoic acid derivatives which are effective in therapy of lipid metabolism abnormality, diabetes and the like as a human peroxisome proliferators-activated receptor (PPAR) agonist, in particular, as an agonist against human PPARα isoform, and addition salts thereof, and pharmaceutical compositions containing these compounds. BACKGROUND ART [0002] Peroxisome proliferators-activated receptor (PPAR) is a ligand-dependent transcription factor belonging to a nuclear receptor super-family likewise steroid receptors, retinoid receptors, thyroid receptors and the like. The receptor includes three isoforms (type α, type γ and type δ (or type β)), which have been identified in various animal species (Non-patent document 1). Among these, PPARα distributes in liver, kidney or the like having high fatty acid catabolic ability (Non-patent document 2), and positively or negatively controls expression of genes involved in fatty a...

Claims

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Application Information

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IPC IPC(8): A61K31/426A61K31/445A61K31/5375A61K31/55A61P3/10C07D211/36C07D223/00C07D277/02C07D413/00
CPCC07D211/22C07D211/26C07D417/12C07D211/56C07D211/60C07D211/42A61P3/10A61P3/04A61P3/06A61P43/00A61P5/50A61P9/10A61K31/427A61K31/4523
Inventor NOMURA, MASAHIROTAKANO, YASUOYUMOTO, KAZUHIROSHINOZAKI, TAKEHIROISOGAI, SHIGEKIMURAKAMI, KOJI
Owner KYORIN PHARMA CO LTD
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